Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

被引:28
作者
Chu, K. Y. [1 ]
Li, H. [1 ]
Wada, K. [2 ]
Johnson, J. D. [1 ]
机构
[1] Univ British Columbia, Dept Cellular & Physiol Sci, Diabet Res Grp, Lab Mol Signaling Diabet, Vancouver, BC V6T 1Z3, Canada
[2] Natl Ctr Neurol & Psychiat Kodaira, Natl Inst Neurosci, Dept Degenerat Neurol Dis, Tokyo, Japan
关键词
Apoptosis; Parkinson's disease; Type; 2; diabetes; Ubiquitin proteasome system; AXONAL DYSTROPHY GAD; ENDOPLASMIC-RETICULUM STRESS; PROTEASOME PATHWAY; TUMOR-SUPPRESSOR; OXIDATIVE STRESS; GENE-EXPRESSION; PROTEIN; PGP9.5; DEGRADATION; APOPTOSIS;
D O I
10.1007/s00125-011-2323-1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1 (-/-) mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1 (-/-) mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1 (-/-) islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.
引用
收藏
页码:128 / 140
页数:13
相关论文
共 51 条
[1]   α-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro [J].
Burre, Jacqueline ;
Sharma, Manu ;
Tsetsenis, Theodoros ;
Buchman, Vladimir ;
Etherton, Mark R. ;
Suedhof, Thomas C. .
SCIENCE, 2010, 329 (5999) :1663-1667
[2]   β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes [J].
Butler, AE ;
Janson, J ;
Bonner-Weir, S ;
Ritzel, R ;
Rizza, RA ;
Butler, PC .
DIABETES, 2003, 52 (01) :102-110
[3]   Interaction and colocalization of PGP9.5 with JAB1 and p27Kip1 [J].
Caballero, OL ;
Resto, V ;
Patturajan, M ;
Meerzaman, D ;
Guo, MZ ;
Engles, J ;
Yochem, R ;
Ratovitski, E ;
Sidransky, D ;
Jen, J .
ONCOGENE, 2002, 21 (19) :3003-3010
[4]   Proteomic analysis of brain proteins in the gracile axonal dystrophy (gad) mouse, a syndrome that emanates from dysfunctional ubiquitin carboxyl-terminal hydrolase L-1, reveals oxidation of key proteins [J].
Castegna, A ;
Thongboonkerd, V ;
Klein, J ;
Lynn, BC ;
Wang, YL ;
Osaka, H ;
Wada, K ;
Butterfield, DA .
JOURNAL OF NEUROCHEMISTRY, 2004, 88 (06) :1540-1546
[5]   A MULTIUBIQUITIN CHAIN IS CONFINED TO SPECIFIC LYSINE IN A TARGETED SHORT-LIVED PROTEIN [J].
CHAU, V ;
TOBIAS, JW ;
BACHMAIR, A ;
MARRIOTT, D ;
ECKER, DJ ;
GONDA, DK ;
VARSHAVSKY, A .
SCIENCE, 1989, 243 (4898) :1576-1583
[6]   Staring, a novel E3 ubiquitin-protein ligase that targets syntaxin 1for degradation [J].
Chin, LS ;
Vavalle, JP ;
Li, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (38) :35071-35079
[7]   Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases [J].
Choi, J ;
Levey, AI ;
Weintraub, ST ;
Rees, HD ;
Gearing, M ;
Chin, LS ;
Li, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (13) :13256-13264
[8]   ATP-Citrate Lyase Reduction Mediates Palmitate-induced Apoptosis in Pancreatic Beta Cells [J].
Chu, Kwan Yi ;
Lin, Yalin ;
Hendel, Alon ;
Kulpa, Jerzy E. ;
Brownsey, Roger W. ;
Johnson, James D. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (42) :32606-32615
[9]   β-Cell Dysfunctional ERAD/Ubiquitin/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide-Induced UCH-L1 Deficiency [J].
Costes, Safia ;
Huang, Chang-jiang ;
Gurlo, Tatyana ;
Dava, Marie ;
Matveyenko, Meksey V. ;
Rizza, Robert A. ;
Butler, Alexandra E. ;
Butler, Peter C. .
DIABETES, 2011, 60 (01) :227-238
[10]   Degradation of cAMP-Responsive Element-Binding Protein by the Ubiquitin-Proteasome Pathway Contributes to Glucotoxicity in β-Cells and Human Pancreatic Islets [J].
Costes, Safia ;
Vandewalle, Brigitte ;
Tourrel-Cuzin, Cecile ;
Broca, Christophe ;
Linck, Nathalie ;
Bertrand, Gyslaine ;
Kerr-Conte, Julie ;
Portha, Bernard ;
Pattou, Francois ;
Bockaert, Joel ;
Dalle, Stephane .
DIABETES, 2009, 58 (05) :1105-1115